Monocyte/macrophages are critical elements of the inflammatory response. Monocytes emigrate from the peripheral circulation and enter into an extravascular region of extracellular connective tissue matrices. In this milieu, monocytes ingest and kill invading pathogens. Pathogenic Gram-positive and Gram- negative bacteria require opsonization to be recognized, phagocytized and killed by monocyte/macrophages. Activation of the complement system by these microorganism initiates the inflammatory response, that results in the deposition of the serum opsonins C3b, iC3b, and IgG on the bacterial surface. The specific plasma membrane receptors to which these opsonized bacteria bind, (CR1, CR3, and FcR, respectively) have been identified and structurally characterized. In vitro and in vivo studies have shown that phagocytosis via FcR is a constitutive property of phagocytes and that CR1- and CR3-mediated phagocytosis is regulated developmentally. The overall goal of this research proposal is to understand how monocyte/macrophage bactericial activity is regulated at sites of inflammation. Therefore, he proposes to study regulation by extracellular connective tissue matrices, complement components, and cytokines of monocyte bactericidal activity for opsonized bacteria. The project has three specific aims: 1) to determine the roles of CR1, CR3, and FcR in mediating the phagocytosis and killing of opsonized bacteria by monocytes adherent to type I collagen gels; 2) to investigate the mechanism by which adherence to type I collagen gels activates monocyte complement receptors for phagocytosis; 3) to quantify the phagocytic and bactericidal activity of monocytes adherent to connective tissue matrices formed from mixtures of fibronectin, laminin, and vitronectin in collagen gels; to determine the additional regulatory effects of complement components and cytokines on phagocyte function in this milieu; and to determine if modulation of phagocyte function is mediated through regulation of complement receptor and FcR function, or by activation of the respiratory burst.